Tetracylic immunomodulatory compounds

ABSTRACT

The present invention relates to novel heterocyclic compounds, to methods for their preparation, to compositions containing them, and to methods and use for clinical treatment of medical conditions which may benefit from immunomodulation, including rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis. More particularly, the present invention relates to novel heterocyclic compounds, which are CD80 antagonists capable of inhibiting the interactions between CD80 and CD28.

The present invention relates to novel heterocyclic compounds, tomethods for their preparation, to compositions containing them, and tomethods and use for clinical treatment of medical conditions which maybenefit from immunomodulation, including rheumatoid arthritis, multiplesclerosis, diabetes, asthma, transplantation, systemic lupuserythematosis and psoriasis. More particularly the present inventionrelates to novel heterocyclic compounds, which are CD80 antagonistscapable of inhibiting the interactions between CD80 and CD28.

BACKGROUND OF THE INVENTION

The immune system possesses the ability to control the homeostasisbetween the activation and inactivation of lymphocytes through variousregulatory mechanisms during and after an immune response. Among theseare mechanisms that specifically inhibit and/or turn off an immuneresponse. Thus, when an antigen is presented by MHC molecules to theT-cell receptor, the T-cells become properly activated only in thepresence of additional co-stimulatory signals. In the absence ofaccessory signals there is no lymphocyte activation and either a stateof functional inactivation termed anergy or tolerance is induced, or theT-cell is specifically deleted by apoptosis.

One such co-stimulatory signal involves interaction of CD80 onspecialised antigen-presenting cells with CD28 on T-cells, which hasbeen demonstrated to be essential for full T-cell activation. (Lenschowet al. (1996) Annu. Rev. Immunol., 14, 233-258)

A paper by Erbe et al, in J. Biol. Chem. Vol. 277, No. 9, pp 7363-7368,describes three small molecule ligands which bind to CD80, and inhibitbinding of CD80 to CD28 and CTLA4. Two of the disclosed ligands arefused pyrazolones of structures A and B:

Compound C is disclosed in U.S. Pat. No. 4,312,870 as one of severalpsychoactive compounds but without biological data. Some relatedcompounds are described by A. Carotti in Bioorganic & MedicinalChemistry 6 (1998) 389-399, and from their data it is obvious that thecarboxylic acid substituent greatly diminishes biologic activitymeasured as affinity for the CNS benzodiazepine receptor.

EP 0354693A1 (Boots) discloses immunomodulatory compounds of generalstructure D but does not include structures wherein R7 and/or R8 areCOOH or contain a COOH group.

Similarly EP 0354694A1 (Boots) discloses immunomodulatory compounds ofgeneral structure E but here are not included structures wherein R6and/or R7 are COOH or contain a COOH group.

Also, WO9111448 (Boots) discloses immunomodulatory compounds of generalstructure F but here are not included structures wherein R7 and/or R8and R8′ are COOH or contain a COOH group.

DESCRIPTION OF THE INVENTION

According to the present invention there is provided a compound offormula (I) or a pharmaceutically or veterinarily acceptable saltthereof:

wherein

-   -   Z represents a carboxylic acid group (—COOH) or an ester        thereof;    -   R₁ and R₃ independently represent H; F; Cl; Br; —NO₂; —CN; C₁-C₆        alkyl optionally substituted by F or Cl; or C₁-C₆ alkoxy        optionally substituted by F;    -   R₂ represents optionally substituted C₃-C₇ cycloalkyl or        optionally substituted phenyl;    -   Y represents —O—, —S—, N-oxide, or —N(R₅)— wherein R₅ represents        H or C₁-C₆ alkyl;    -   X represents a bond or a group selected from; a divalent C₁-C₆        alkylene radical, NHC(O) C₁₋₅ alkyl, NHC(O) CH₂—O—CH₂ or        C(O)—NH— (amino acid residue);

Compounds of general formula (I) are CD80 antagonists. They inhibit theinteraction between CD80 and CD28 and thus the activation of T cells,thereby modulating the immune response.

Accordingly the invention also includes:

(i) a compound of formula (I) or a pharmaceutically or veterinarilyacceptable salt thereof for use in the treatment of conditions whichbenefit from immunomodulation.

(ii) the use of a compound of formula (I) or a pharmaceutically orveterinarily acceptable salt thereof in the manufacture of a medicamentfor the treatment of conditions which benefit from immunomodulation.

(iii) a method of immunomodulation in mammals, including humans,comprising administration to a mammal in need of such treatment animmunomodulatory effective dose of a compound of formula (I) or apharmaceutically or veterinarily acceptable salt thereof.

(iv) a pharmaceutical or veterinary composition comprising a compound offormula (I) or a pharmaceutically or veterinarily acceptable saltthereof together with a pharmaceutically or veterinarily acceptableexcipient or carrier.

Conditions which benefit from immunomodulation include:

-   Acute disseminated encephalomyelitis-   Adrenal insufficiency-   Allergic angiitis and granulomatosis-   Amylodosis-   Ankylosing spondylitis-   Asthma-   Autoimmune Addison's disease-   Autoimmune alopecia-   Autoimmune chronic active hepatitis-   Autoimmune hemolytic anemia-   Autoimmune neutropenia-   Autoimmune thrombocytopenic purpura-   Behçet's disease-   Cerebellar degeneration-   Chronic active hepatitis-   Chronic inflammatory demyelinating polyradiculoneuropathy-   Chronic neuropathy with monoclonal gammopathy-   Classic polyarteritis nodosa-   Congenital adrenal hyperplasia-   Cryopathies-   Dermatitis herpetiformis-   Diabetes-   Eaton-Lambert myasthenic syndrome-   Encephalomyelitis-   Epidermolysis bullosa acquisita-   Erythema nodosa-   Gluten-sensitive enteropathy-   Goodpasture's syndrome-   Guillain-Barre syndrome-   Hashimoto's thyroiditis-   Hyperthyrodism-   Idiopathic hemachromatosis-   Idiopathic membranous glomerulonephritis-   Isolated vasculitis of the central nervous system-   Kawasaki's disease-   Minimal change renal disease-   Miscellaneous vasculitides-   Mixed connective tissue disease-   Multifocal motor neuropathy with conduction block-   Multiple sclerosis-   Myasthenia gravis-   Opsoclonus-myoclonus syndrome-   Pemphigoid-   Pemphigus-   pernicious anemia-   Polymyositis/dermatomyositis-   Post-infective arthritides-   Primary biliary sclerosis-   Psoriasis-   Reactive arthritides-   Reiter's disease-   Retinopathy-   Rheumatoid arthritis-   Sclerosing cholangitis-   Sjögren's syndrome-   Stiff-man syndrome-   Subacute thyroiditis-   Systemic lupus erythematosis-   Systemic necrotizing vasculitides-   Systemic sclerosis (scleroderma)-   Takayasu's arteritis-   Temporal arteritis-   Thromboangiitis obliterans-   Type I and type II autoimmune polyglandular syndrome-   Ulcerative colitis-   Uveitis-   Wegener's granulomatosis

As used herein, the term “ester” refers to a group of the form —COOR,wherein R is a radical notionally derived from the alcohol ROH. Examplesof ester groups include the physiologically hydrolysable esters such asthe methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, andbenzyl esters.

As used herein the term “alkylene” refers to a straight or branchedalkyl chain having two unsatisfied valencies, for example —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—, —CH(CH₂CH₃)CH₂CH₂CH₃, and —C(CH₃)₃.

Unless otherwise specified in the context in which it occurs, the term“substituted” as applied to any moiety herein means substituted with upto four substituents, each of which independently may be (C₁-C₆)alkyl,trifluoromethyl, (C₁-C₆)alkoxy (including the special case where a ringis substituted on adjacent ring C atoms by methylenedioxy orethylenedioxy), trifluoromethoxy, (C₁-C₆)alkylthio, phenyl, benzyl,phenoxy, hydroxy, mercapto, amino, fluoro, chloro, bromo, cyano, nitro,oxo, —COOH, —SO₂OH, —CONH₂, —SO₂NH₂, —COR^(A), —COOR^(A), —SO₂OR^(A),—NHCOR^(A), —NHSO₂R^(A), —CONHR^(A), —SO₂NHR^(A), —NHR^(A),—NR^(A)R^(B), —CONR^(A)R^(B) or —SO₂NR^(A)R^(B) wherein R^(A) and R^(B)are independently a (C₁-C₆)-alkyl group, a (C₃-C₇) cycloalkyl group orC₂-C₆ alkoxy group. In the case where “substituted” means substituted bybenzyl or phenoxy, the phenyl ring thereof may itself be substitutedwith any of the foregoing, except phenyl or benzyl.

As used herein the unqualified term “carbocyclyl” or “carbocyclic”refers to a 5-8 membered ring whose ring atoms are all carbon.

Some compounds of the invention contain one or more chiral centresbecause of the presence of asymmetric carbon atoms. The presence ofasymmetric carbon atoms gives rise to stereoisomers or diastereoisomerswith R or S stereochemistry at each chiral centre. The inventionincludes all such stereoisomers and diastereoisomers and mixturesthereof.

Salts of salt forming compounds of the invention include physiologicallyacceptable acid addition salts for example hydrochlorides,hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates,phosphates, acetates, citrates, succinates, lactates, tartrates,fumarates and maleates; and base addition salts, for example sodium,potassium, magnesium, and calcium salts.

In the compounds of the invention the following are examples of theseveral structural variables:

Z may be, for example a carboxylic acid group (—COOH) or a methyl orbenzyl ester thereof. Presently —COOH is preferred.

R₁ may be, for example, H, F, Cl, methyl, methoxy, or methylenedioxy.Currently it is preferred that R₁ is H, F, or Cl;

R₂ may be, for example cyclopropyl, phenyl, or fluoro-, chloro-, methyl,methoxy-, nitro-, or amino-substituted phenyl;

R₃ may be, for example, H, F, Cl, methyl, methoxy, or methylenedioxy.Currently it is preferred that R₃ is H, F, or Cl;

Y may be, for example, —O—, —S—, or —N(R₅)— wherein R₅ represents H ormethyl. —NH— is presently preferred.

X may be, for example a bond, or a —CH₂— or —CH₂CH₂-radical. A bond ispresently preferred.

As mentioned above, the invention includes pharmaceutical or veterinarycomposition comprising a compound of formula (I) or a pharmaceuticallyor veterinarily acceptable salt thereof together with a pharmaceuticallyor veterinarily acceptable excipient or carrier. In such compositions,it will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the causative organism and severity ofthe particular disease undergoing therapy. Optimum dose levels andfrequency of dosing will be determined by clinical trial.

The compounds with which the invention is concerned may be prepared foradministration by any route consistent with their pharmacokineticproperties. The orally administrable compositions may be in the form oftablets, capsules, powders, granules, lozenges, liquid or gelpreparations, such as oral, topical, or sterile parenteral solutions orsuspensions. Tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

For topical application to the skin, the drug may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

For topical application to the eye, the drug may be made up into asolution or suspension in a suitable sterile aqueous or non aqueousvehicle. Additives, for instance buffers such as sodium metabisulphiteor disodium edeate; preservatives including bactericidal and fungicidalagents such as phenyl mercuric acetate or nitrate, benzalkonium chlorideor chlorhexidine, and thickening agents such as hypromellose may also beincluded.

The active ingredient may also be administered parenterally in a sterilemedium. Depending on the vehicle and concentration used, the drug caneither be suspended or dissolved in the vehicle. Advantageously,adjuvants such as a local anaesthetic, preservative and buffering agentscan be dissolved in the vehicle.

Compounds of the invention may be prepared by synthetic methods known inthe literature, from compounds which are commercially available or areaccessible from commercially available compounds. For example, compoundsof formula (I) wherein Y is N may be prepared by reaction of a compoundof formula (II) with an hydrazide of formula (III):

wherein Z1 is a carboxylic acid or an esterified carboxylic acid. Estercompounds (I) may of course be hydrolysed to the free acid.

The following Examples illustrate the preparation of compounds of theinvention:Synthetic Route Followed:

Typical experimental R₂=4-nitro phenyl, Ar₁=4-b enzoic acid methyl ester

EXAMPLE 1

Step 1

2-(4-Nitro-phenyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethylester

Sodium hydride (0.92 g, 0.023 mol; 60% suspension in mineral oil) wasadded portionwise to a stirred solution of3-(4-nitrophenyl)-3-oxopropionic acid ethyl ester (5.46 g, 0.023 mol) indimethylacetamide (20 mL) at room temperature. A solution of isatoicanhydride (3.4 g, 0.02 mol) in dimethylacetamide (20 mL) was added tothis solution. The reddish mixture was stirred at 120° C. for 30 min andthen the solvent was concentrated in vacuo. The crude solid waspartitioned between water and ethyl acetate and the organic phase thenseparated. The combined organic extracts were dried over sodium sulfateand concentrated in vacuo to leave a residue which was washed once withcold tert-butylmethyl ether to yield2-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethylester (1.61 g, 28%) as a white solid, LCMS m/z 339.33 [M+H]⁺ @ R_(T)1.16 min, 100% purity.

Step 2

4-Chloro-2-(4-nitro-phenyl)-quinoline-3-carboxylic acid ethyl ester

Phosphorus oxychloride (8 mL, 0.087 mol) was added in one portion to2-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethylester (3.7 g, 0.0109 mol) and the mixture was heated at 95° C. for 90min. The resulting light brown solution was added dropwise to avigorously stirred ice-cold solution of sodium hydroxide (500 mL; 0.7M). The aqueous suspension was extracted with ethyl acetate and thecombined organic extracts were dried and concentrated in vacuo to leave4-chloro-2-(4-nitophenyl)-quinoline-3-carboxylic acid ethyl ester (3.8g, 98%) as a white solid, LCMS m/z 357.21 [M+H]⁺ @ R_(T) 1.94 min, 98%purity.

Step 3

4-[4-(4-Nitro-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoicacid methyl ester

4-Chloro-2-(4-nitrophenyl)-quinoline-3-carboxylic acid ethyl ester (2.86g, 0.008 mol) and 4-hydrazino-benzoic acid methyl ester hydrochloride(1.7 g, 0.008 mol) were stirred in n-butanol (70 mL) at 120° C. for 24h. The bright orange suspension was diluted with tert-butylmethyl ether,filtered, washed with cold heptane and left to dry under suction toyield4-[4-(4-nitrophenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]quinolin-2-yl]-benzoicacid methyl ester (2.7 g, 76%) as an orange solid, LCMS m/z 441.35[M+H]⁺ @ R_(T) 1.66 min: 84% purity.

EXAMPLE 24-[4-(4-Amino-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoicacid methyl ester

4-[4-(4-Nitro-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoicacid methyl ester (2.6 g, 5.9 mmol) and Pd/C (100 mg, 10%) weresuspended in ethanol (150 mL) and acetic acid (6 mL) and stirred underhydrogen for 24 h. The resulting yellow-orange suspension was dilutedwith DMF (50 mL) and filtered. The solvent was removed in vacuo to leavea residue which was washed with methanol to give4-[4-(4-amino-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoicacid methyl ester (2.0 g, 82%) as a pale orange solid, LCMS m/z 411.39[M+H]⁺ @ R_(T) 1.27 min, 79% purity.

EXAMPLE 34-[4-(4-Nitro-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoicacid

Prepared using the procedure described above, using 4-hydrazinobenzoicacid. LCMS m/z 427.34 [M+H]⁺ @ R_(T) 1.38 min, 74% purity

EXAMPLE 43-[4-(4-Nitro-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzoicacid

Prepared by methods analogous to Example 3. LCMS m/z 427.37 [M+H]⁺ @R_(T) 1.28 min, 96% purity.

EXAMPLE 54-[4-(3-Nitro-phenyl)-3-oxo-3,5-dihydro-pyrazolo[4,3-c]-quinolin-2-yl]-benzoicacid

Prepared by methods analogous to Example 3. LCMS m/z 427.38 [M+H]⁺ @R_(T) 1.33 min, 88% purity. δ_(H)(400 MHz, (CD₃)₂SO) 12.8 (1H, s), 8.85(1H, t J 2.0), 8.54 (1H, dd J₁ 7.1 J₂ 2.0), 8.35 (4H, m), 8.02 (1H, s),8.0 (1H, s), 7.94 (1H, t J 8.0), 7.84 (1H, d J 7.9), 7.74 (1H, t, J7.1), 7.6 (1H, t J 7.1).

EXAMPLE 64-[4-(4-Methoxyphenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]quinolin-2-yl]benzoicacid methyl ester

Prepared by methods analogous to Example 1. LCMS m/z 426.34 [M+H]⁺ @R_(T) 1.71 min, 82% purity. δ_(H)(400 MHz, (CD₃)₂SO) 8.2 (2H, d J 9.0),8.05 (1H, dd J₁ 8.0 J₂ 1.1), 7.82 (2H, d J 9.0), 7.77 (2H, d J 9.0),7.65 (1H, d J 9.0), 7.48 (1H, td J₁ 8.2 J₂ 1.3), 7.34 (1H, td J₁ 7.0 J₂1.1), 6.98 (2H, d J 9.0).

EXAMPLE 74-[4-(4-Methoxyphenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]-quinolin-2-yl]benzoicacid

Prepared using the procedure analogous to Example 1. LCMS m/z 412.28[M+H]⁺ @ R_(T) 1.28 min, 88% purity.

EXAMPLE 84-[4-(4-Aminophenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]-quinolin-2-yl]benzoicacid methyl ester

Prepared using the procedure analogous to Example 1. LCMS m/z 397.36[M+H]⁺ @ R_(T) 1.11 min, 63% purity.

EXAMPLE 93-[4-(4-Methoxyphenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]-quinolin-2-yl]benzoicacid methyl ester

Prepared using the procedure analogous to Example 1, using3-hydrazinobenzoic acid. LCMS m/z 412.3 [M+H]⁺ @ R_(T) 1.29 min, 86%purity.

EXAMPLE 104-[4-(3-Nitrophenyl)-3-oxo-3,5-dihydropyrazolo[4,3-c]-quinolin-2-yl]benzoicacid methyl ester

Prepared by methods analogous to Example 1. LCMS m/z 441.37 [M+H]⁺ @R_(T) 1.80 min, 82% purity.

EXAMPLE 114-[3-Oxo-4-(2,4,5-trifluorophenyl)-3,5-dihydropyrazolo-[4,3-c]quinolin-2-yl]benzoicacid

Prepared by methods analogous to Example 3. LCMS m/z 436.36 [M+H]⁺ @R_(T) 1.30 min, 83% purity.

BIOLOGICAL EXAMPLE

The examples described above were tested in a cell free Homogenous TimeResolved Fluorescence (HTRF) assay to determine their activity asinhibitors of the CD80-CD28 interaction.

In the assay, europium and allophycocyanin (APC) are associated withCD28 and CD80 indirectly (through anti-body linkers) to form a complex,which brings the europium and APC into close proximity to generate asignal. The complex comprises the following six proteins: fluorescentlabel 1, linker antibody 1, CD28 fusion protein, CD80 fusion protein,linker antibody 2, and fluorescent label 2. The table below describesthese reagents in greater detail. Fluorescent Anti-Rabbit IgG labelledwith Europium label 1 (1 μg/ml) Linker Rabbit IgG specific for mouse Fcantibody 1 fragment (3 μg/ml) CD28 fusion CD28 - mouse Fc fragmentfusion protein protein (0.48 μg/ml) CD80 fusion CD80 mouse Fab fragment(C215) fusion protein protein (1.9 μg/ml) Linker GαMκ-biotin:biotinylated goat IgG antibody 2 specific for mouse kappa chain (2μg/ml) Fluorescent SA-APC: streptavidin labelled label 2 allophycocyanin(8 μg/ml)

On formation of the complex, europium and APC are brought into proximityand a signal is generated.

Non-specific interaction was measured by substituting a mouse Fabfragment (C215) for the CD80 mouse Fab fragment fusion protein (1.9μg/ml). The assay was carried out in black 384 well plates in a finalvolume of 30 μl. Assay buffer: 50 mM Tris-HCl, 150 mM NaCl pH7.8,containing 0.1% BSA (w/v) added just prior to use.

Compounds were added to the above reagents in a concentration seriesranging between 100 μM-1.7 nM. The reaction was incubated for 4 hours atroom temperature. Dual measurements were made using a Wallac Victor 1420Multilabel Counter. First measurement: excitation 340 nm, emission 665nm, delay 50 μs, window time 200 μs. second measurement: excitation 340nm, emission 615 nm, delay 50 μs, window time 200 μs. Counts wereautomatically corrected for fluorescence crossover, quenching andbackground.

By way of illustration, the IC₅₀ results for the compounds of Examples5, 7 and 9 were 8.6 μM, 3.4 μM and 4.6 μM respectively.

1. A compound of formula (I) or a pharmaceutically or veterinarilyacceptable salt thereof:

wherein Z represents a carboxylic acid group (—COOH) or an esterthereof; R₁ and R₃ independently represent H; F; Cl; Br; —NO₂; —CN;C₁-C₆ alkyl optionally substituted by F or Cl; or C₁-C₆ alkoxyoptionally substituted by F; R₂ represents optionally substituted C₃-C₇cycloalkyl or optionally substituted phenyl; Y represents —O—, —S—,N-oxide, or —N(R₅)— wherein R₅ represents H or C₁-C₆ alkyl; and Xrepresents a bond or a group selected from; a divalent C₁-C₆ alkyleneradical, NHC(O)C₁₋₅ alkyl or NHC(O)CH₂—O—CH₂.
 2. A compound as claimedin claim 1 wherein X is a bond or a —CH₂— or —CH₂CH₂— radical.
 3. Acompound as claimed in claim 1 wherein Z is —COOH.
 4. A compound asclaimed in claim 1 wherein R₁ is H, F, Cl, methyl, methoxy, ormethylenedioxy.
 5. A compound as claimed in claim 1 wherein R₂ iscyclopropyl, phenyl, or fluoro-, chloro-, methyl, methoxy-, nitro-, oramino-substituted phenyl.
 6. A compound as claimed in claim 1 wherein R₃is H, F, Cl, methyl, methoxy, or methylenedioxy.
 7. A compound asclaimed in claim 1 wherein Y is —N(R₅)— wherein R₅ represents H ormethyl.
 8. (canceled)
 9. A medicament for the treatment of conditionswhich benefit from immunomodulation comprising an effective dose of acompound according to claim
 1. 10. A method of immunomodulation inmammals, including humans, comprising administering to a mammal in needof such treatment an immunomodulatory effective dose of a compound asclaimed in claim
 1. 11. A pharmaceutical or veterinary compositioncomprising a compound as claimed in claim 1 together with apharmaceutically or veterinarily acceptable excipient or carrier.
 12. Acompound as claimed in claim 2 wherein Z is —COOH.
 13. A compound asclaimed in claim 2 wherein R₁ is H, F, Cl, methyl, methoxy, ormethylenedioxy.
 14. A compound as claimed in claim 2 wherein R₂ iscyclopropyl, phenyl, or fluoro-, chloro-, methyl, methoxy-, nitro-, oramino-substituted phenyl.
 15. A compound as claimed in claim 2 whereinR₃ is H, F, Cl, methyl, methoxy, or methylenedioxy.
 16. A compound asclaimed in claim 2 wherein Y is —N(R₅)— wherein R₅ represents H ormethyl.
 17. A method of immunomodulation in mammals, including humans,comprising administering to a mammal in need of such treatment animmunomodulatory effective dose of a compound as claimed in claim
 2. 18.A method of immunomodulation in mammals, including humans, comprisingadministering to a mammal in need of such treatment an immunomodulatoryeffective dose of a compound as claimed in claim
 3. 19. A pharmaceuticalor veterinary composition comprising a compound as claimed in claim 2together with a pharmaceutically or veterinarily acceptable excipient orcarrier.
 20. A pharmaceutical or veterinary composition comprising acompound as claimed in claim 3 together with a pharmaceutically orveterinarily acceptable excipient or carrier.
 21. A pharmaceutical orveterinary composition comprising a compound as claimed in claim 4together with a pharmaceutically or veterinarily acceptable excipient orcarrier.